Temperature controlled sol-gel co-condensation

ABSTRACT

Provided according to some embodiments of the invention are methods of making co-condensed macromolecules that include forming a reaction mixture by combining at least one reactant and at least one reagent at a first temperature at which the at least one reactant is substantially unreactive in the presence of the at least one reagent; raising the temperature of the reaction mixture to a second temperature at which the at least one reactant is reactive in the presence of the at least one reagent, wherein the reaction of the at least one reactant in the presence of the at least one reagent produces co-condensed macromolecules such as co-condensed silica macromolecules.

CLAIM OF PRIORITY

This application is a continuation of U.S. patent application Ser. No.13/946,186, now U.S. Pat. No. 8,937,143, filed on Jul. 19, 2013, whichis a continuation under 35 U.S.C. §111(a) of International PatentApplication No. PCT/US2012/022048, filed on Jan. 20, 2012, which claimsthe benefit, under 35 U.S.C. §119 of U.S. Provisional Patent ApplicationSer. No. 61/434,478 filed Jan. 20, 2011, the disclosure of each of whichis incorporated herein by reference as if set forth in its entirely.

STATEMENT OF GOVERNMENT SUPPORT

This invention was made with government support under grant number1013531 awarded by the National Science Foundation. The United StatesGovernment has certain rights in this invention.

BACKGROUND OF THE INVENTION

Silica co-condensation is useful in material science to makepolysiloxane macromolecules with specific chemical and physicalproperties. It may be desirable to control physical and chemicalcompositions of silica macromolecules, particularly those silicamacromolecules used in healthcare products such as medical devices andpharmaceutical compositions.

In silica co-condensation, different silane monomers may be mixed priorto the addition of catalyst and/or additional reagents that may initiatethe condensation. The silane mixture may then be added at a controlledspeed in a reactor that holds the catalyst and/or the other reagents.Once the silane monomer mixture is combined with the catalyst and/orother reagents, the co-condensation reaction begins. However, it may bedifficult to obtain a homogeneous solution via controlling the speed ofaddition and/or the agitation of the mixture, particularly if the silanemixture includes basic monomers such as aminosilanes, which mayself-catalyze during the co-condensation reaction. Inhomogeneity of thesolution may affect the composition and properties of the resultingco-condensed macromolecules.

Methods that decrease or eliminate the problem of inhomogeneity in theco-condensation reaction mixture would be desirable.

SUMMARY OF THE INVENTION

Provided according to some embodiments of the invention are methods ofmaking co-condensed silica macromolecules that include forming areaction mixture by combining at least one reactant and at least onereagent at a first temperature at which the at least one reactant issubstantially unreactive in the presence of the at least one reagent;raising the temperature of the reaction mixture to a second temperatureat which the at least one reactant is reactive in the presence of the atleast one reagent, wherein the reaction of the at least one reactant inthe presence of the at least one reagent produces co-condensed silicamacromolecules.

In some embodiments, the at least one reactant includes at least onesilane monomer. In some embodiments, the at least one reactant includesat least two silane monomers. In some embodiments, a first of the atleast two silane monomers includes an inorganic silane monomer and asecond of the at least two silane monomers includes an organic silanemonomer. In some embodiments, the at least one silane monomer includes adiazeniumdiolated aminosilane.

In some embodiments, the at least one reagent includes a base, and insome embodiments, the at least one reagent includes a solvent.

In some embodiments, the first temperature is less than −5° C., and insome embodiments, less than −10° C. In some embodiments, the secondtemperature is greater than 0° C., and in some embodiments, greater than5° C.

In some embodiments of the invention, methods further include (a)maintaining the reaction temperature of the reaction mixture at thesecond temperature; and/or (b) raising the temperature of the reactionmixture to a third temperature that is not less than the secondtemperature. In some embodiments, the third temperature is greater thanthe second temperature and raising the reaction temperature of thereaction mixture includes increasing the second temperature to the thirdtemperature at a rate of between about 0.1° C. per minute and 10° C. perminute.

In some embodiments, methods further include increasing uniformity orhomogeneity of the reaction mixture prior to raising the temperature ofthe reaction mixture. In some embodiments, methods of increasinguniformity of the reaction mixture include at least one of stirring,mixing, mechanical agitation, high shear homogenization, and/orultrasound.

In some embodiments of the invention, the co-condensed silicamacromolecules include nanoparticles and/or microparticles. In someembodiments, the method provides greater than one gram of co-condensedsilica per 0.5 liters of reaction mixture. Furthermore, in someembodiments, methods provide a yield of co-condensed silicamacromolecules of greater than 10%.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

The foregoing and other aspects of the present invention will now bedescribed in more detail with respect to the description andmethodologies provided herein. It should be appreciated that theinvention can be embodied in different forms and should not be construedas limited to the embodiments set forth herein. Rather, theseembodiments are provided so that this disclosure will be thorough andcomplete, and will fully convey the scope of the invention to thoseskilled in the art.

The terminology used in the description of the invention herein is forthe purpose of describing particular embodiments only and is notintended to be limiting of the invention. As used in the description ofthe embodiments of the invention and the appended claims, the singularforms “a”, “an” and “the” are intended to include the plural forms aswell, unless the context clearly indicates otherwise. Also, as usedherein, “and/or” refers to and encompasses any and all possiblecombinations of one or more of the associated listed items. Furthermore,the term “about,” as used herein when referring to a measurable valuesuch as an amount of a compound, dose, time, temperature, and the like,is meant to encompass variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1%of the specified amount. It will be further understood that the terms“comprises” and/or “comprising,” when used in this specification,specify the presence of stated features, integers, steps, operations,elements, and/or components, but do not preclude the presence oraddition of one or more other features, integers, steps, operations,elements, components, and/or groups thereof. Unless otherwise defined,all terms, including technical and scientific terms used in thedescription, have the same meaning as commonly understood by one ofordinary skill in the art to which this invention belongs.

All patents, patent applications and publications referred to herein areincorporated by reference in their entirety. In the event of conflictingterminology, the present specification is controlling.

The embodiments described in one aspect of the present invention are notlimited to the aspect described. The embodiments may also be applied toa different aspect of the invention as long as the embodiments do notprevent these aspects of the invention from operating for its intendedpurpose.

Chemical Definitions

As used herein the term “alkyl” refers to C₁₋₂₀ inclusive, linear (i.e.,“straight-chain”), branched, or cyclic, saturated or at least partiallyand in some cases fully unsaturated (i.e., alkenyl and alkynyl)hydrocarbon chains, including for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, octyl, ethenyl,propenyl, butenyl, pentenyl, hexenyl, octenyl, butadienyl, propynyl,butynyl, pentynyl, hexynyl, heptynyl, and allenyl groups. “Branched”refers to an alkyl group in which a lower alkyl group, such as methyl,ethyl or propyl, is attached to a linear alkyl chain. Exemplary branchedalkyl groups include, but are not limited to, isopropyl, isobutyl,tert-butyl. “Lower alkyl” refers to an alkyl group having 1 to about 8carbon atoms (i.e., a C₁₋₈ alkyl), e.g., 1, 2, 3, 4, 5, 6, 7, or 8carbon atoms. “Higher alkyl” refers to an alkyl group having about 10 toabout 20 carbon atoms, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or20 carbon atoms. In certain embodiments, “alkyl” refers, in particular,to C₁₋₅ straight-chain alkyls. In other embodiments, “alkyl” refers, inparticular, to C₁₋₅ branched-chain alkyls.

Alkyl groups can optionally be substituted (a “substituted alkyl”) withone or more alkyl group substituents, which can be the same ordifferent. The term “alkyl group substituent” includes but is notlimited to alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl,aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio,carboxyl, alkoxycarbonyl, oxo, and cycloalkyl. There can be optionallyinserted along the alkyl chain one or more oxygen, sulfur or substitutedor unsubstituted nitrogen atoms, wherein the nitrogen substituent ishydrogen, lower alkyl (also referred to herein as “alkylaminoalkyl”), oraryl.

Thus, as used herein, the term “substituted alkyl” includes alkylgroups, as defined herein, in which one or more atoms or functionalgroups of the alkyl group are replaced with another atom or functionalgroup, including for example, alkyl, substituted alkyl, halogen, aryl,substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino,dialkylamino, sulfate, and mercapto.

The term “aryl” is used herein to refer to an aromatic substituent thatcan be a single aromatic ring, or multiple aromatic rings that are fusedtogether, linked covalently, or linked to a common group, such as, butnot limited to, a methylene or ethylene moiety. The common linking groupalso can be a carbonyl, as in benzophenone, or oxygen, as indiphenylether, or nitrogen, as in diphenylamine. The term “aryl”specifically encompasses heterocyclic aromatic compounds. The aromaticring(s) can comprise phenyl, naphthyl, biphenyl, diphenylether,diphenylamine and benzophenone, among others. In particular embodiments,the term “aryl” means a cyclic aromatic comprising about 5 to about 10carbon atoms, e.g., 5, 6, 7, 8, 9, or 10 carbon atoms, and including 5-and 6-membered hydrocarbon and heterocyclic aromatic rings.

The aryl group can be optionally substituted (a “substituted aryl”) withone or more aryl group substituents, which can be the same or different,wherein “aryl group substituent” includes alkyl, substituted alkyl,aryl, substituted aryl, aralkyl, hydroxyl, alkoxyl, aryloxyl,aralkyloxyl, carboxyl, acyl, halo, nitro, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, acyloxyl, acylamino, aroylamino,carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylthio, alkylthio,alkylene, and —NR¹R″, wherein R¹ and R″ can each be independentlyhydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and aralkyl.

Thus, as used herein, the term “substituted aryl” includes aryl groups,as defined herein, in which one or more atoms or functional groups ofthe aryl group are replaced with another atom or functional group,including for example, alkyl, substituted alkyl, halogen, aryl,substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino,dialkylamino, sulfate, and mercapto. Specific examples of aryl groupsinclude, but are not limited to, cyclopentadienyl, phenyl, furan,thiophene, pyrrole, pyran, pyridine, imidazole, benzimidazole,isothiazole, isoxazole, pyrazole, pyrazine, triazine, pyrimidine,quinoline, isoquinoline, indole, carbazole, and the like.

“Cyclic” and “cycloalkyl” refer to a non-aromatic mono- or multicyclicring system of about 3 to about 10 carbon atoms, e.g., 3, 4, 5, 6, 7, 8,9, or 10 carbon atoms. The cycloalkyl group can be optionally partiallyunsaturated. The cycloalkyl group also can be optionally substitutedwith an alkyl group substituent as defined herein, oxo, and/or alkylene.There can be optionally inserted along the cyclic alkyl chain one ormore oxygen, sulfur or substituted or unsubstituted nitrogen atoms,wherein the nitrogen substituent is hydrogen, alkyl, substituted alkyl,aryl, or substituted aryl, thus providing a heterocyclic group.Representative monocyclic cycloalkyl rings include cyclopentyl,cyclohexyl, and cycloheptyl. Multicyclic cycloalkyl rings includeadamantyl, octahydronaphthyl, decalin, camphor, camphane, andnoradamantyl.

“Alkoxyl” refers to an alkyl-O— group wherein alkyl is as previouslydescribed. The term “alkoxyl” as used herein can refer to, for example,methoxyl, ethoxyl, propoxyl, isopropoxyl, butoxyl, f-butoxyl, andpentoxyl. The term “oxyalkyl” can be used interchangeably with“alkoxyl”. In some embodiments, the alkoxyl has 1, 2, 3, 4, or 5carbons.

“Aralkyl” refers to an aryl-alkyl group wherein aryl and alkyl are aspreviously described, and included substituted aryl and substitutedalkyl. Exemplary aralkyl groups include benzyl, phenylethyl, andnaphthylmethyl.

“Alkylene” refers to a straight or branched bivalent aliphatichydrocarbon group having from 1 to about 20 carbon atoms, e.g., 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbonatoms. The alkylene group can be straight, branched or cyclic. Thealkylene group also can be optionally unsaturated and/or substitutedwith one or more “alkyl group substituents.” There can be optionallyinserted along the alkylene group one or more oxygen, sulfur orsubstituted or unsubstituted nitrogen atoms (also referred to herein as“alkylaminoalkyl”), wherein the nitrogen substituent is alkyl aspreviously described. Exemplary alkylene groups include methylene(—CH₂—); ethylene (—CH₂—CH₂—); propylene (—(CH₂)₃—); cyclohexylene(—C₆H₁₀—); —CH═CH—CH═CH—; —CH═CH—CH₂—; wherein each of q and r isindependently an integer from 0 to about 20, e.g., 0, 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and R ishydrogen or lower alkyl; methylenedioxyl (—O—CH₂—O—); and ethylenedioxyl(—O—(CH₂)₂—O—). An alkylene group can have about 2 to about 3 carbonatoms and can further have 6-20 carbons.

“Arylene” refers to a bivalent aryl group. An exemplary arylene isphenylene, which can have ring carbon atoms available for bonding inortho, meta, or para positions with regard to each other, i.e.,respectively. The arylene group can also be napthylene. The arylenegroup can be optionally substituted (a “substituted arylene”) with oneor more “aryl group substituents” as defined herein, which can be thesame or different.

“Aralkylene” refers to a bivalent group that contains both alkyl andaryl groups. For example, aralkylene groups can have two alkyl groupsand an aryl group (i.e., -alkyl-aryl-alkyl-), one alkyl group and onearyl group (i.e., -alkyl-aryl-) or two aryl groups and one alkyl group(i.e., -aryl-alkyl-aryl-).

The term “amino” refers to nitrogen-containing groups —NR¹R², wherein R¹and R² can each be independently hydrogen, alkyl, substituted alkyl,aryl, substituted aryl, and aralkyl, alkylene, arylene, aralkylene.Thus, “amine” as used herein can refer to a primary amine, a secondaryamine, or a tertiary amine. In some embodiments, one R of an amino groupcan be a cation stabilized diazeniumdiolate (i.e., NONO⁻X⁺). The terms“cationic amine” and “quaternary amine” refer to an amino group havingan additional R group (—N⁺R¹R²R³)X⁻, such as a hydrogen or an alkylgroup bonded to the nitrogen. Thus, cationic and quaternary amines carrya positive charge, and so may be associated with a counterion (X″), suchas a halide or other known counterion for quaternary amines.

The term “alkylamine” refers to the -alkyl-NH₂ group.

The term “carbonyl” refers to the —(C═O)— group.

The term “carboxyl” refers to the —COOH group and the term “carboxylate”refers to an anion formed from a carboxyl group, i.e., —COO⁻.

The terms “halo”, “halide”, or “halogen” as used herein refer to fluoro,chloro, bromo, and iodo groups.

The term “hydroxyl” and “hydroxy” refer to the —OH group.

The term “hydroxyalkyl” refers to an alkyl group substituted with an —OHgroup.

The term “mercapto” or “thio” refers to the —SH group. The term “silyl”refers to groups comprising silicon atoms (Si).

The term “silane” refers to any compound that includes four organicgroups, such as including any of the organic groups described herein(e.g., alkyl, aryl and alkoxy), bonded to a silicon atom.

As used herein the term “alkoxysilane” refers to a silane that includesone, two, three, or four alkoxy groups bonded to a silicon atom. Forexample, tetraalkoxysilane refers to Si(OR)₄, wherein R is alkyl. Eachalkyl group can be the same or different. An “alkylalkoxylsilane” refersto an alkoxysilane wherein one or more of the alkoxy groups has beenreplaced with an alkyl group. Thus, an alkylalkoxysilane comprises atleast one alkyl-Si bond.

The term “fluorinated silane” refers to an alkylsilane wherein one ofthe alkyl groups is substituted with one or more fluorine atoms.

The term “cationic or anionic silane” refers to an alkylsilane whereinone of the alkyl groups is further substituted with an alkyl substituentthat has a positive (i.e., cationic) or a negative (i.e. anionic)charge, or can become charged (i.e., is ionizable) in a particularenvironment (i.e., in vivo).

The term “silanol” refers to a Si—OH group.

Provided herein according to some embodiments of the invention aremethods of making co-condensed silica macromolecules. In someembodiments of the invention, provided are methods of makingco-condensed silica macromolecules that include forming a reactionmixture by combining at least one reactant and at least one reagent at afirst temperature at which the at least one reactant is substantiallyunreactive in the presence of the at least one reagent (also referred toherein as “the first temperature”); and raising the temperature of thereaction mixture to a second temperature at which the at least onereactant is reactive in the presence of the at least one reagent (alsoreferred to herein as “the second temperature”). As such, the reactionof the at least one reactant in the presence of the at least one reagentproduces co-condensed silica macromolecules.

Reactants and Reagents

As described above, the reaction mixture includes at least one reactantand at least one reagent. As used herein, the term “reactant” refers toa compound that is consumed during the reaction, while the term“reagent” refers to a compound or substance that is added to thereaction mixture to facilitate the reaction but is not consumed.

Any suitable reactant may be used. However, in some embodiments of theinvention, the at least one reactant includes a silane monomer. Anysuitable silane monomer may be used. For example, in some embodiments,the silane may be an inorganic silane and in some embodiments, thesilane, is an organic silane. Furthermore, in some embodiments, mixturesof inorganic and/or organic silanes may be used. However, in someembodiments, the silane monomer may include alkoxysilane, such as atetraalkoxysilane having the formula Si(OR)₄, wherein R is an alkylgroup. The R groups can be the same or different. In some embodimentsthe tetraalkoxysilane is selected as tetramethyl orthosilicate (TMOS) ortetraethyl orthosilicate (TEOS). In some embodiments, the silane monomermay include aminoalkoxysilane. In some embodiments, theaminoalkoxysilane has the formula: R″—(NH—R′)_(n)—Si(OR)₃, wherein R isalkyl, R′ is alkylene, branched alkylene, or aralkylene, n is 1 or 2,and R″ is selected from the group consisting of alkyl, cycloalkyl, aryl,and alkylamine.

In some embodiments, the aminoalkoxysilane can be selected fromN-(6-aminohexyl)aminopropyltrimethoxysilane (AHAP3);N-(2-aminoethyl)-3-aminopropyltrimethoxysilane (AEAP3);(3-trimethoxysilylpropyl)di-ethylenetriamine (DET3);(aminoethylaminomethyl)phenethyltrimethoxysilane (AEMP3);[3-(methylamino)propyl]trimethoxysilane (MAP3);N-butylamino-propyltrimethoxysilane (n-BAP3);t-butylamino-propyltrimethoxysilane (t-BAP3);N-ethylaminoisobutyltrimethoxysilane (EAiB3);N-phenylamino-propyltrimethoxysilane (PAP3); andN-cyclohexylaminopropyltrimethoxysilane (cHAP3).

In some embodiments, the aminoalkoxysilane has the formula: NH[R′—Si(OR)₃]₂, wherein R is alkyl and R′ is alkylene. In someembodiments, the aminoalkoxysilane can be selected frombis(3-triethoxysilylpropyl)amine, bis-[3-(trimethoxysilyl)propyl]amineand bis-[(3-trimethoxysilyl)propyl]ethylenediamine.

In some embodiments of the invention, the nitric oxide donor may beformed from an aminoalkoxysilane by a pre-charging method, and theco-condensed siloxane network may be synthesized from the condensationof a silane mixture that includes an alkoxysilane and theaminoalkoxysilane to form a nitric oxide donor modified co-condensedsiloxane network. As used herein, the “pre-charging method” means thataminoalkoxysilane is “pretreated” or “precharged” with nitric oxideprior to the co-condensation with alkoxysilane. In some embodiments, theprecharging nitric oxide may be accomplished by chemical methods. Inanother embodiment, the “pre-charging” method can be used to createco-condensed siloxane networks and materials more densely functionalizedwith NO-donors.

In some embodiments, as described herein above, the aminoalkoxysilane isprecharged for NO-release and the amino group is substituted by adiazeniumdiolate. Therefore, in some embodiments, the aminoalkoxysilanehas the formula: R″—N(NONO⁻X⁺)—R—Si(OR)₃, wherein R is alkyl, R′ isalkylene or aralkylene, R″ is alkyl or alkylamine, and X⁺ is a cationselected from the group consisting of Na⁺, K⁺ and Li⁺.

In some embodiments of the invention, the co-condensed siloxane networkfurther includes at least one crosslinkable functional moiety of formula(R¹)_(x)(R²)_(y)SiR³, wherein R¹ and R² is each independently C₁₋₅ alkylor C₁₋₅ alkoxyl, X and Y is each independently 0, 1, 2, or 3, and X+Yequal to 3, and R³ is a crosslinkable functional group. In a furtherembodiment, R¹ is C₁₋₃ alkoxyl, and R₂ is methyl. In another embodiment,R₃ is selected from the group consisting of acrylo, alkoxy, epoxy,hydroxy, mercapto, amino, isocyano, carboxy, vinyl and urea. R³ impartsan additional functionality to the silica which results in amultifunctional device. Yet, in another embodiment, the crosslinkablefunctional moiety is selected from the group consisting ofmethacryloxymethyltrimethoxysilane, methacryloxypropyltrimethoxysilane,methacryloxypropyltriethoxysilane, 3-acryloxypropyl)trimethoxysilane,N-(3-methyacryloxy-2-hydroxypropyl)-3-aminopropyltriethoxysilane,5,6-epoxyhexyltriethoxysilane, 2-(3,4-epoxycyclohexyl)ethyltrimethoxysilane, 3-glycidoxypropyl)trimethoxysilane,3-aminopropyltrimethoxysilane, 3-aminopropyltriethoxysilane,3-isocyanatopropyltriethoxysilane, 3-mercaptopropyltrimethoxysilane,mercaptopropyltriethoxysilane, 11-mercaptoundecyltrimethoxysilane,2-cyanoethyltriethoxysilane, ureidopropyltriethoxysilane,ureidopropyltrimethoxysilane, vinylmethyldiethoxysilane,vinylmethyldimethoxysilane, vinyltriethoxysilane, vinyltrimethoxysilane,vinyltriisopropoxysilane and vinyltris(2-methoxyethoxy)silane. In someembodiments, R³ may be used to cross-link the NO-donor modified silicawith or within polymeric matrices.

Additional silane monomers are described in U.S. Publication No.2009/0214618, U.S. patent application Ser. No. 13/256,928, filed Sep.15, 2011; and U.S. Provisional Application No. 61/526,918, filed Aug.24, 2011. The content of each of these references is incorporated hereinby reference in its entirety.

Any suitable reagent may be included in the reaction mixture, including,for example, catalysts, solvents, and other additives. Any suitablecatalyst may be used, including mixtures of catalyst. However, in someembodiments, the catalyst includes a basic catalyst such as ammoniumhydroxide, dimethyl amine, diethyl amine, or other alkyl amines withformula of NR¹R²R³, in which R¹, R², R³ are each independently hydrogenor C₁₋₅ alkyl groups. Other examples of basic catalysts includeinorganic salts that have high solubility in wet alcoholic solvents suchas sodium acetate, sodium bicarbonate and etc. The catalyst may bepresent at any suitable concentration in the reaction mixture. However,in some embodiments, the catalyst is present at a concentration in arange of 0.1 M to 5.0 M, in some embodiments, in a range of 0.8 M to 1.2M, and in some embodiments, in a range of 1-1.1 M.

Any suitable solvent, including mixtures of solvents, may be included inthe reaction mixture. Examples of solvents include acetone, methylalcohol, ethanol, isopropanol, butyl alcohol, ethyl acetate, dimethylisosorbide, propylene glycol, glycerol, ethylene glycol, polyethyleneglycol, diethylene glycol monoethyl ether or mixtures thereof. Inparticular examples, the solvent includes ethanol and/or isopropanol.

Any suitable additional additives/reagents may be added, and suchadditional reagents are known to those of skill in the art. Additionalexamples may be found in U.S. Publication No. 2009/0214618, the contentsof which are hereby incorporated by reference in its entirety.

Forming the Reaction Mixture

The reaction mixture is formed by combining at least one reactant and atleast one reagent at a first temperature. Any suitable method of forminga reaction mixture may be used, including simple addition of thecomponents or via a device such as a syringe pump, whereby thecombination may occur at a specified rate. Additionally, the differentcomponents of the reaction mixture may be combined in any suitablesequence.

At the first temperature, the at least one reactant is substantiallyunreactive in the presence of the at least one reagent. As used herein,the term “substantially unreactive” means that no visually detectablereaction occurs. In particular embodiments, the first temperature isless than −5° C., in some embodiments, less than −10° C., in someembodiments, less than −10° C., in some embodiments, less than −20° C.,and in some embodiments, less than −25° C.

One purpose of forming the reaction mixture at the first temperature isto allow the at least one reactant and the at least one reagent to forma more homogeneous reaction mixture prior to initiation of theco-condensation reaction. As such, combinations of silane monomersand/or other reactants may be added together at the first temperature,provided that the co-condensation reaction does not occur when themonomers are combined. The first temperature may vary depending onidentity and the concentration of the at least one reactant and the atleast one reagent. In some embodiments, all of the at least one reactantand/or the at least one reagent are added at the first temperature.However, in some embodiments, some of the at least one reactant and/orthe at least one reagent can be added at the second, third and/or othertemperature.

In some embodiments, the reaction mixture may be physically homogenized.The reaction mixture may be homogenized by any suitable method,including via mechanical stirring, homogenization devices and the like.In some embodiments, the reaction mixture is homogenized to becomesubstantially homogenous before raising the temperature. As used herein,the term “substantially homogeneous” refers to a reaction mixturewherein the ratio of constituents per unit volume of the mixturesdiffers by no more than 30% throughout the mixture, in some embodimentsby no more than 20%, and in further embodiments, by no more than 10%, 5%or 1%. In some embodiments, the reaction mixture is maintained at thefirst temperature while being mixed/homogenized. Alternatively, in someembodiments, the temperature may be changed to a different temperaturewherein the reactants remain substantially unreactive while the reactionmixture is homogenized.

Raising the Temperature

At some time, for example, when the reaction mixture appears to behomogenous, the temperature of the reaction mixture may be raised tobegin the co-condensed reaction. The reaction temperature may be raisedto any suitable temperature, including temperatures wherein the reactionoccurs slowly and/or temperatures wherein the co-condensation reactionoccurs quickly. In some embodiments, the reaction mixture is raised to atemperature wherein the co-condensation reaction is sufficientlycomplete in less than 5 hours, in some embodiments, in less than 3hours, and in some embodiments, in less than 1 hour. The term“sufficiently complete” means that while residual monomer may remain,substantially all of the at least one reactant has reacted. In someembodiments, the reaction mixture is heated to a temperature of greaterthan 0° C., in some embodiments, greater than 5° C., and in someembodiments, greater than 20° C.

In some embodiments of the invention, methods further include (a)maintaining the reaction temperature of the reaction mixture at thesecond temperature; and/or (b) raising the temperature of the reactionmixture to a third temperature, such as a temperature that is not lessthan the second temperature. In some embodiments, the third temperatureis less than 50° C., and in some embodiments, less than 40° C. In someembodiments, raising the reaction temperature of the reaction mixturefrom the second temperature to the third temperature includes increasingthe second temperature to the third temperature at a rate of betweenabout 0.1° C. per minute and 10° C. per minute.

Co-condensed Silica Macromolecules

Also provided according to some embodiments of the invention areco-condensed silica macromolecules, including NO-releasing co-condensedsilica macromolecules, formed by a method described herein. In somecases, the methods described herein may produce co-condensed silicamacromolecules having improved chemical and physical properties. Forexample, in some embodiments, the co-condensed silica macromolecules mayhave improved size and composition uniformity and homogeneity.

For example, in some embodiments, co-condensed silica macromolecules mayhave relatively narrow particle size distribution. Additionally, it hasbeen discovered that when a labile active pharmaceutical entity (e.g., aNO-releasing functional group such as a diazeniumdiolate) is loaded onone silica monomer, the resulting silica particles may retain higherpotency and higher yield with the present process as compared to atraditional process. Additional advantages of methods according toembodiments of the invention may include one or more of the following:process equipment may be simplified; processes may be easier to scale-upwith less in-process control; costs of production may be decreased;solvent waste may be decreased; and silica particles may be producedwith higher yields of precipitated silica and/or higher recovery ofsilane reactants as product.

In some embodiments, the yield of the co-condensation reaction, asmeasured by the ratio of the mass of co-condensed silica product to themass of silane input materials, is greater than 10%. In someembodiments, the ratio is 40% or greater, 50% or greater, 60% orgreater, 70% or greater or greater than 80%.

In addition to yields, the reaction volume per unit of product producedmay be reduced according to embodiments of the present invention. Forexample, prior to use of the current inventive process, a typical basecatalyzed silane co-condensation process that was scaled up in a 20liter reactor would generally produce 20-40 grams per batch. Thereaction volume was generally between 0.50-1.0 liter per gram of productproduced, with a resulting solid weight recovery at less than 4%. Incontrast, the temperature controlled co-condensations according to someembodiments of the present invention can be scaled up to 4.5 liters andproduce over 200 grams of product per batch.

Methods according to embodiments of the invention not only may providebetter control and programming in process scale up, but they may alsosignificantly cut the reaction volume per unit product to 0.017-0.021liter per gram of product produced. As such, the process capacity of aset manufacturing facility may be increased, while production cost,waste generation and environmental impact may significantly decrease.Accordingly, some embodiments of the present invention provide areaction volume per unit of precipitated silica of less than 0.5 litersper gram, in further embodiments, less than 0.25 liters per gram, insome embodiments, less than 0.1 liters per gram, in some embodiments,less than 0.05 liters per gram and, in some embodiments, less than 0.025liters per gram.

The term “NO-releasing co-condensed silica macromolecules” refers to astructure synthesized from monomeric silane constituents that results ina larger molecular framework with a molar mass of at least 500 Da and anominal diameter ranging from 0.1 nm-100 μm and may comprise theaggregation of two or more macromolecules, whereby the macromolecularstructure is further modified with an NO donor group. For example, insome embodiments, the NO donor group may include diazeniumdiolate nitricoxide functional groups. In some embodiments, the NO donor group mayinclude S-nitrosothiol functional groups.

In some embodiments of the invention, the NO-releasing polysiloxanemacromolecules may be in the form of NO-releasing particles, such asthose described in U.S. Publication No. 2009/0214618, U.S. patentapplication Ser. No. 13/256,928, filed Sep. 15, 2011; and U.S.Provisional Application No. 61/526,918, filed Aug. 24, 2011.

EXAMPLES Example 1 Synthesis of Co-Condensed Silica ofN-Methylaminopropyltrimethoxysilane (MAP3) and Tetraethoxysilane (TEOS)

In a 250 ml round bottom flask, MAP3 (1.74 g, 9.0 mmol) was mixed with20 ml of Isopropanol. The flask was flashed with nitrogen and then putin an ice/salt bath to chill to −5° C. while stirred magnetically. Intothe cold mixture, TEOS (1.88 g, 9.0 mmol) was added. After thetemperature stabilized, ammonium hydroxide solution (0.3 ml, 28%) wasadded. The homogeneous mixture was warmed slowly to room temperature.Solid started to precipitate after 10 minutes at room temperature. Thereaction was kept for 2 hours, before the mixture was separated withcentrifuge. The solid was washed with dry Ethanol 20 mL twice. The solidwas dried overnight at room temperature under vacuum. The reactionproduced 2.0 g of off white silica particles.

Example 2 Synthesis of Co-condensed Silica ofN-methylaminopropyltrimethoxysilane-Diazeniumdiolate (MAP3-NO) and TEOS,Lab Scale

Both reactors in this reaction were flashed with nitrogen. In a 2 literround bottom flask, 500 ml of MeOH solution of sodiummethylaminopropyltrimethoxysilaneNONOate (0.31 mol of total silane) waschilled to −15° C. in a dry ice bath. Ethanol (1000 mL) was added intothe mixture. Wait till the temperature stabilized to −15° C.,tetraethoxysilane (65.1 g, 0.31 mol) was added. After the temperaturestabilized, DI Water (25 g, 1.39 mol) was added. Ammonium hydroxideaqueous solution (120 ml, 28%) was pre-chilled to −15° C. and added intothe mixture. The mixture was a homogenous clear solution at this point.The content was transferred to a 2 liter jacketed reactor with mechanicstirring. The jacket temperature was set at 14° C. The temperature ofthe mixture increased to the equilibrium temperature of 14° C. in about15 minutes. The stirring speed was controlled to be over 800 RPM. Solidstarted to precipitate after 10-20 minutes at stabilized temperature.The reaction was kept for 3 hours, before the mixture was isolated withnitrogen protected filtration set, using the fine glassfiber filterpaper. The wet cake was washed with dry Ethanol 300 mL twice. The solidwas air-dried with nitrogen for an hour before transferred to a traydrier. The wet cake weight 122.40 g, and was dried overnight at roomtemperature under vacuum. The reaction produced 73.3 g ofdiazeniumdiolate-functionalized co-condensed silica macromolecule.

Example 3 Synthesis of Co-condensed Silica ofN-MethylAminoPropylTrimethoxySilane-Diazeniumdiolate (MAP3-NO) and TEOS,Manufacturing Scale

The 20 liter jacketed reactor was equipped with an air motor, nitrogeninlet and a circulator. Ethanol (6240 g) was dispensed into the reactor.The agitator air pressure was turned on to at least 60 psig. The reactorwas chilled to −13° C. over at least 60 minutes. Once the internaltemperature reached target, 3645 g of MeOH solution of sodiummethylaminopropyltrimethoxysilaneNONOate (2.62 mol of total silane) wascharged. The jacket temperature was kept at −13-(−15)° C. Water(Deionized, 202 g, 11.2 mol) was charged followed by TetraEthoxySilane(545 g, 2.62 mol) was added. After the temperature stabilized to −13°C., pre-chilled Ammonium Hydroxide aqueous solution (920 g, 28%) addedinto the mixture. The mixture was a homogenous clear solution at thispoint. Waited till nucleation started to show, for another 5-20 minutes,set the jacket temperature to 10° C. at a speed of 2° C. a minute. Thereaction was kept for at least 2 but not more than 3 hours. The slurrywas then discharged and filtered with nitrogen protected filtration set,using the fine glassfiber filter paper. The wet cake was washed with dryEthanol 1000 mL twice. The solid was air-dried with nitrogen for an hourbefore transferred to a tray drier. The wet cake weight 1100 g, and wasdried overnight at room temperature under vacuum. The reaction produced650 g of diazeniumdiolate-functionalized co-condensed silicamacromolecule.

Many modifications and other embodiments of the inventions set forthherein will come to mind to one skilled in the art to which theseinventions pertain having the benefit of the teachings presented in theforegoing descriptions and the associated drawings. Therefore, it is tobe understood that the inventions are not to be limited to the specificembodiments disclosed and that modifications and other embodiments areintended to be included within the scope of the appended claims.Although specific terms are employed herein, they are used in a genericand descriptive sense only and not for purposes of limitation.

That which is claimed:
 1. A method of making NO-releasing co-condensedsilica macromolecules, comprising: forming a reaction mixture bycombining at least one silane and at least one reagent at a firsttemperature of less than −5° C.; and raising the temperature of thereaction mixture to a second temperature that is greater than 0° C. andless than 40° C., thereby producing NO-releasing co-condensed silicamacromolecules.
 2. The method of claim 1, wherein the temperature of thereaction mixture is raised at a rate of 10° C. per minute or less. 3.The method of claim 1, wherein the at least one silane comprises aninorganic silane monomer and/or an organic silane monomer.
 4. The methodof claim 1, wherein the at least one silane comprises at least twosilane monomers.
 5. The method of claim 1, wherein the at least onesilane comprises a tetraalkoxysilane having the formula: Si(OR)₄,wherein R is an alkyl group.
 6. The method of claim 1, wherein the atleast one silane comprises an aminoalkoxysilane having the formula:R″—(NH—R′)_(n)—Si(OR)₃, wherein R is an alkyl group, R′ is an alkylenegroup, a branched alkylene group, or an aralkylene group, R″ is selectedfrom the group consisting of alkyl, cycloalkyl, aryl, and alkylamine,and n is 1 or
 2. 7. The method of claim 1, wherein the at least onesilane comprises an aminoalkoxysilane having the formula:NH—[R′—Si(OR)₃]₂, wherein R is alkyl and R′ is alkylene.
 8. The methodof claim 1, wherein the at least one silane comprises anaminoalkoxysilane that is selected from the group consisting ofbis(3-triethoxysilylpropyl)amine, bis-[3-(trimethoxysilyl)propyl]amine,bis-[(3-trimethoxysilyl)propyl]ethylenediamine, and any combinationthereof.
 9. The method of claim 1, wherein the at least one reagentcomprises a base.
 10. The method of claim 9, wherein the base comprisesammonium hydroxide.
 11. The method of claim 1, wherein the reactionmixture further comprises at least one solvent.
 12. The method of claim11, wherein the solvent comprises an alcohol.
 13. The method of claim 1,wherein the first temperature is less than −10° C.
 14. The method ofclaim 1, further comprising increasing uniformity of the reactionmixture prior to raising the temperature of the reaction mixture. 15.The method of claim 14, wherein increasing uniformity of the reactionmixture comprises at least one of stirring, mixing, mechanicalagitation, high shear homogenization, and/or ultrasound.
 16. The methodof claim 1, wherein the method provides greater than one gram ofNO-releasing co-condensed silica macromolecules per 0.5 liters ofreaction mixture.
 17. The method of claim 1, wherein the method providesa yield of NO-releasing co-condensed silica macromolecules of greaterthan 10%.
 18. A method of making NO-releasing co-condensed silicamacromolecules, comprising: forming a reaction mixture by combining atetraalkoxysilane that is selected from the group consisting oftetramethyl orthosilicate (TMOS), tetraethyl orthosilicate (TEOS), andany combination thereof, an N-diazeniumdiolate functionalizedaminoalkoxysilane, and at least one reagent at a first temperature ofless than −5° C., wherein the N-diazeniumdiolate functionalizedaminoalkoxysilane is formed from an aminoalkoxysilane that is selectedfrom the group consisting of N-(6-aminohexyl)aminopropyltrimethoxysilane(AHAP3), N-(2-aminoethyl)-3-aminopropyltrimethoxysilane (AEAP3),(3-trimethoxysilylpropyl)di-ethylenetriamine (DET3);(aminoethylaminomethyl)phenethyltrimethoxysilane (AEMP3),[3-(methylamino)propyl]trimethoxysilane (MAP3),N-butylamino-propyltrimethoxysilane (n-BAP3);t-butylamino-propyltrimethoxysilane (t-BAP3),N-ethylaminoisobutyltrimethoxysilane (EAiB3),N-phenylamino-propyltrimethoxysilane (PAP3),N-cyclohexylaminopropyltrimethoxysilane (cHAP3), and any combinationthereof; and raising the temperature of the reaction mixture to a secondtemperature that is greater than 0° C. and less than 40° C., therebyproducing NO-releasing co-condensed silica macromolecules.
 19. Themethod of claim 18, wherein the temperature of the reaction mixture israised at a rate of 10° C. per minute or less.
 20. The method of claim18, wherein the N-dizeniumdiolate functionalized aminoalkoxysilanecomprises diazeniumdiolated-N-methyl(aminopropyl)trimethoxysilane. 21.The method of claim 20, wherein the method provides greater than onegram of NO-releasing co-condensed silica macromolecules per 0.5 litersof reaction mixture.
 22. The method of claim 20, wherein the methodprovides a yield of NO-releasing co-condensed silica macromolecules ofgreater than 10%.
 23. The method of claim 18, wherein the firsttemperature is less than −10° C.
 24. The method of claim 18, furthercomprising increasing uniformity of the reaction mixture prior toraising the temperature of the reaction mixture.
 25. The method of claim24, wherein increasing uniformity of the reaction mixture comprises atleast one of stirring, mixing, mechanical agitation, high shearhomogenization, and/or ultrasound.
 26. The method of claim 18, whereinthe at least one reagent comprises a base.
 27. The method of claim 26,wherein the base comprises ammonium hydroxide.
 28. The method of claim18, wherein the reaction mixture further comprises at least one solvent.29. The method of claim 28, wherein the solvent comprises an alcohol.